The 12-month results from a multicenter trial monitoring CellCept® (mycophenolate mofetil) in combination with calcineurin inhibitors (CNIs) in renal transplantation was presented today at the American Transplant Congress (ATC). The study results showed that a reduced level of CNI with a therapeutic monitored dose of CellCept is not inferior to that of a fixed dose of CellCept, and the standard-dose of CNI as it relates to biopsy-proven acute rejection (BPAR) and other end points.
The lower CNI dose regimen studied to avoid long-term side effects of chronic administration of CNI, facilitated a higher CellCept dosing without an overall increase in adverse events, and with a trend toward preservation of kidney function versus the standard-dose CNI regimens. As transplant patients are living longer, studies suggest that therapies such as CNIs can cause impairment of kidney function, damage to the blood vessels, and filtering capacity of the kidneys.
“The Opticept trial was designed to examine the impact of monitored CellCept dosing to enable a low dose CNI regimen with fewer complications and preservation of efficacy in preventing rejection,” said Robert Gaston, M.D., lead investigator, University of Alabama at Birmingham (UAB), Birmingham, AL. “The 12-month study results are very encouraging and additional follow-up may provide insights into the long-term impact of these short-term findings.”
About the Study
Opticept is a two-year open-label, prospective, randomized, multicenter study involving 720 single-organ renal allograft recipients administered either concentration-controlled CellCept and a reduced level of CNI, a concentration-controlled CellCept and the standard level of CNI, or a fixed-dose of CellCept and the standard level CNI.
Antibody induction and/or corticosteroids were administered according to center practice. Primary endpoints were the proportion of patients with treatment failure (BPAR, graft loss, and death) and mean percent change in calculated glomerular filtration rate (GFR; Nankivell equation) at 12 months. Safety endpoints were incidences of adverse events and serious adverse events. Non-inferiority for treatment failure was tested. Baseline characteristics did not differ among treatment groups with living donors accounting for approximately 50 percent of grafts. Eighty-two percent received tacrolimus (Tac) and 18 percent cyclosporine (CyA). CNI doses and levels were significantly lower in the reduced level of CNI. CellCept doses were greater in CyA-treated subjects in all groups.
Study Results
After 12 months, treatment failure resulted in 20.6 percent (50/243) in the concentration-controlled CellCept and a reduced level of CNI group, compared to 28.7 percent (68/237) in the concentration-controlled CellCept and the standard level of CNI group, and 26.7 percent (64/240) in the fixed-dose of CellCept and the standard level CNI group.
Five patients (2.1 percent) in the concentration-controlled CellCept and a reduced level of CNI group died; two patients (0.8 percent) died in the concentration-controlled CellCept and the standard level of CNI group; and five patients (2.1 percent) died in the fixed-dose of CellCept and the standard level CNI group.
Groups Patients Graft Loss BPAR Lost to f/u
MMFCC/CNIRL 243 5 (2.1%) 15 (6.2%) 25 (10.3%)
MMFCC/CNISL 237 4 (1.7%) 23 (9.7%) 23 (9.6%)
MMFFD/CNIRL 240 4 (1.7%) 23 (9.6%) 32 (13.3%)
Note: events are mutually exclusive because only first event counted/patient
Serum creatinine tended to lower at 12 months in the Tac versus CyA treated patients and in the concentration-controlled CellCept and reduced level of CNI group (p=0.08). The stability of renal function over time was greatest in this group as well. Despite higher CellCept doses in the concentration-controlled CellCept and reduced level of CNI group (p<0.001) at most time points, significantly fewer CellCept withdrawals occurred versus the other two groups.
CellCept is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. CellCept should be used concomitantly with cyclosporine and corticosteroids.
Important Safety Information:
WARNING:
Immunosuppression may lead to increased susceptibility to infection and possible development of lymphoma. Only physicians experienced in immunosuppressive therapy and management of renal, cardiac or hepatic transplant patients should use CellCept. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
Female users of childbearing potential must use contraception. Physicians should inform female patients that CellCept use during pregnancy is associated with increased rates of pregnancy loss and congenital malformations.
- Patients receiving immunosuppressive regimens involving combinations of drugs, including CellCept, as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin.
- Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections, and sepsis.
- Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with CellCept. Hemiparesis, apathy, confusion, cognitive deficiencies and ataxia were the most frequent clinical features observed. The reported cases generally had risk factors for PML, including treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Consideration should be given to reducing the amount of immunosuppression in patients who develop PML. In transplant patients, physicians should also consider the risk that reduced immunosuppression represents to the graft.
- CellCept can cause fetal harm when administered to a pregnant woman. A patient who is planning a pregnancy should not use CellCept unless she cannot be successfully treated with other immunosuppressant drugs. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Women of childbearing potential (including pubertal girls and peri-menopausal women) taking CellCept must receive contraceptive counseling and use effective contraception. The patient should begin using her chosen contraceptive method 4 weeks prior to starting CellCept therapy. She should continue contraceptive use during therapy and for 6 weeks after stopping CellCept. Two reliable forms of contraception must be used simultaneously unless abstinence is the chosen method. Patients should be aware that CellCept reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness.
- Severe neutropenia [absolute neutrophil count (ANC) <0.5 x 103/mL] developed in up to 2.0% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients receiving CellCept 3 g daily. Patients receiving CellCept should be monitored for neutropenia. If neutropenia develops (ANC < 1.3 x 103/mL), dosing with CellCept should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see DOSAGE AND ADMINISTRATION).
- Gastrointestinal bleeding (requiring hospitalization) has been observed in approximately 3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic transplant patients treated with CellCept 3 g daily.
- Common adverse events that were reported in ≥20% of patients in CellCept group in controlled studies in prevention of renal, cardiac or hepatic allograft rejection are listed in Table 8 of the ADVERSE REACTIONS section of the complete Prescribing Information.
About Roche
Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, one of the world’s leading research-oriented healthcare groups with core businesses in pharmaceuticals and diagnostics. For more than 100 years in the U.S., Roche has been committed to developing innovative products and services that address prevention, diagnosis and treatment of diseases, thus enhancing people's health and quality of life. An employer of choice, in 2007 Roche was named Top Company of the Year by Med Ad News, one of the Top 20 Employers (Science) and ranked the No. 1 Company to Sell For (Selling Power). In previous years, Roche has been named as a Top Company for Older Workers (AARP) and one of the Best Companies to Work For in America (Fortune). For additional information about the U.S. pharmaceuticals business, visit our website http://www.rocheusa.com. Product and treatment information for U.S. healthcare professionals is available at www.RocheExchange.com.
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